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Moldaschl J, Chariyev-Prinz F, Toegel S, Keck M, Hiden U, Egger D, Kasper C. Spheroid trilineage differentiation model of primary mesenchymal stem/stromal cells under hypoxia and serum-free culture conditions. Front Bioeng Biotechnol 2024; 12:1444363. [PMID: 39144480 PMCID: PMC11321963 DOI: 10.3389/fbioe.2024.1444363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 07/12/2024] [Indexed: 08/16/2024] Open
Abstract
Due to their unique properties, human mesenchymal stem/stromal cells (MSCs) possess tremendous potential in regenerative medicine, particularly in cell-based therapies where the multipotency and immunomodulatory characteristics of MSCs can be leveraged to address a variety of disease states. Although MSC-based cell therapeutics have emerged as one of the most promising medical treatments, the clinical translation is hampered by the variability of MSC-based cellular products caused by tissue source-specific differences and the lack of physiological cell culture approaches that closely mimic the human cellular microenvironment. In this study, a model for trilineage differentiation of primary adipose-, bone marrow-, and umbilical cord-derived MSCs into adipocytes, chondrocytes and osteoblasts was established and characterized. Differentiation was performed in spheroid culture, using hypoxic conditions and serum-free and antibiotics-free medium. This platform was characterized for spheroid diameter and trilineage differentiation capacity reflecting functionality of differentiated cells, as indicated by lineage-specific extracellular matrix (ECM) accumulation and expression of distinct secreted markers. The presented model shows spheroid growth during the course of differentiation and successfully supports trilineage differentiation for MSCs from almost all tissue sources except for osteogenesis of umbilical cord-derived MSCs. These findings indicate that this platform provides a suitable and favorable environment for trilineage differentiation of MSCs from various tissue sources. Therefore, it poses a promising model to generate highly relevant biological data urgently required for clinical translation and therefore might be used in the future to generate in vitro microtissues, building blocks for tissue engineering or as disease models.
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Affiliation(s)
- Julia Moldaschl
- Institute of Cell and Tissue Culture Technologies, BOKU University, Vienna, Austria
| | | | - Stefan Toegel
- Karl Chiari Lab for Orthopaedic Biology, Department of Orthopedics and Trauma Surgery, Medical University of Vienna, Vienna, Austria
| | - Maike Keck
- Department of Plastic, Reconstructive and Aesthetic Surgery, Agaplesion Diakonieklinikum Hamburg, Hamburg, Germany
- Klinik für Plastische Chirurgie, Universität zu Lübeck, Lübeck, Germany
| | - Ursula Hiden
- Department of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria
| | - Dominik Egger
- Institute of Cell Biology and Biophysics, Leibniz University Hannover, Hannover, Germany
| | - Cornelia Kasper
- Institute of Cell and Tissue Culture Technologies, BOKU University, Vienna, Austria
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Wang Y, Gao T, Wang B. Application of mesenchymal stem cells for anti-senescence and clinical challenges. Stem Cell Res Ther 2023; 14:260. [PMID: 37726805 PMCID: PMC10510299 DOI: 10.1186/s13287-023-03497-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Accepted: 09/13/2023] [Indexed: 09/21/2023] Open
Abstract
Senescence is a hot topic nowadays, which shows the accumulation of senescent cells and inflammatory factors, leading to the occurrence of various senescence-related diseases. Although some methods have been identified to partly delay senescence, such as strengthening exercise, restricting diet, and some drugs, these only slow down the process of senescence and cannot fundamentally delay or even reverse senescence. Stem cell-based therapy is expected to be a potential effective way to alleviate or cure senescence-related disorders in the coming future. Mesenchymal stromal cells (MSCs) are the most widely used cell type in treating various diseases due to their potentials of self-replication and multidirectional differentiation, paracrine action, and immunoregulatory effects. Some biological characteristics of MSCs can be well targeted at the pathological features of aging. Therefore, MSC-based therapy is also a promising strategy to combat senescence-related diseases. Here we review the recent progresses of MSC-based therapies in the research of age-related diseases and the challenges in clinical application, proving further insight and reference for broad application prospects of MSCs in effectively combating senesce in the future.
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Affiliation(s)
- Yaping Wang
- Clinical Stem Cell Center, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, People's Republic of China
- Clinical Stem Cell Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, People's Republic of China
| | - Tianyun Gao
- Clinical Stem Cell Center, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, People's Republic of China
| | - Bin Wang
- Clinical Stem Cell Center, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, People's Republic of China.
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Song W, Zhao L, Gao Y, Han C, Gao S, Guo M, Bai J, Wang L, Yin W, Wu F, Zhang P. Dual growth factor-modified microspheres nesting human-derived umbilical cord mesenchymal stem cells for bone regeneration. J Biol Eng 2023; 17:43. [PMID: 37430290 DOI: 10.1186/s13036-023-00360-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Accepted: 06/01/2023] [Indexed: 07/12/2023] Open
Abstract
BACKGROUND Modular tissue engineering (MTE) is a novel "bottom-up" approach that aims to mimic complex tissue microstructural features. The constructed micromodules are assembled into engineered biological tissues with repetitive functional microunits and form cellular networks. This is emerging as a promising strategy for reconstruction of biological tissue. RESULTS Herein, we constructed a micromodule for MTE and developed engineered osteon-like microunits by inoculating human-derived umbilical cord mesenchymal stem cells (HUMSCs) onto nHA/PLGA microspheres with surface modification of dual growth factors (BMP2/bFGF). By evaluating the results of proliferation and osteogenic differentiation ability of HUMSCs in vitro, the optimal ratio of the dual growth factor (BMP2/bFGF) combination was derived as 5:5. In vivo assessments showed the great importance of HUMSCs for osteogneic differentiation. Ultimately, direct promotion of early osteo-differentiation manifested as upregulation of Runx-2 gene expression. The vascularization capability was evaluated by tube formation assays, demonstrating the importance of HUMSCs in the microunits for angiogenesis. CONCLUSIONS The modification of growth factors and HUMSCs showed ideal biocompatibility and osteogenesis combined with nHA/PLGA scaffolds. The micromodules constructed in the current study provide an efficient stem cell therapy strategy for bone defect repair.
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Affiliation(s)
- Wenzhi Song
- Department of Stomatology, China-Japan Union Hospital, Jilin University, Changchun, 130031, PR China
| | - Lanlan Zhao
- Department of Stomatology, China-Japan Union Hospital, Jilin University, Changchun, 130031, PR China
| | - Yuqi Gao
- Department of Stomatology, China-Japan Union Hospital, Jilin University, Changchun, 130031, PR China
| | - Chunyu Han
- Department of Stomatology, China-Japan Union Hospital, Jilin University, Changchun, 130031, PR China
| | - Shengrui Gao
- Department of Otorhinolaryngology, First Clinical Hospital of Jilin University, Changchun, 130021, PR China
| | - Min Guo
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, PR China
| | - Jianfei Bai
- Department of Stomatology, China-Japan Union Hospital, Jilin University, Changchun, 130031, PR China
| | - Liqiang Wang
- Department of Ophthalmology, Third Medical Center, Chinese PLA General Hospital, Beijing, 100853, PR China
| | - Wanzhong Yin
- Department of Otorhinolaryngology, First Clinical Hospital of Jilin University, Changchun, 130021, PR China.
| | - Feng Wu
- Foshan Hospital of Traditional Chinese Medicine/Foshan Hospital of TCM, Foshan, China.
| | - Peibiao Zhang
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, PR China
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Zheng X, Gan S, Su C, Zheng Z, Liao Y, Shao J, Zhu Z, Chen W. Screening and preliminary identification of long non-coding RNAs critical for osteogenic differentiation of human umbilical cord mesenchymal stem cells. Bioengineered 2022; 13:6880-6894. [PMID: 35249446 PMCID: PMC8973756 DOI: 10.1080/21655979.2022.2044274] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Human umbilical cord mesenchymal stem cells (hUCMSCs) are attractive therapeutic cells for tissue engineering to treat bone defects. However, how the cells can differentiate into bone remains unclear. Long non-coding RNAs (lncRNAs) are non-coding RNAs that participate in many biological processes, including stem cell differentiation. In this study, we investigated the profiles and functions of lncRNAs in the osteogenic differentiation of hUCMSCs. We identified 343 lncRNAs differentially expressed during osteogenic differentiation, of which 115 were upregulated and 228 were downregulated. We further analyzed these lncRNAs using bioinformatic analyses, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. GO and KEGG pathway analysis showed that ‘intracellular part’ and ‘Phosphatidylinositol signaling system’ were the most correlated molecular function and pathway, respectively. We selected the top 10 upregulated lncRNAs to construct six competing endogenous RNA networks. We validated the impact of the lncRNA H19 on osteogenic differentiation by overexpressing it in hUCMSCs. Overall, our results pave the way to detailed studies of the molecular mechanisms of hUCMSC osteogenic differentiation, and they provide a new theoretical basis to guide the therapeutic application of hUCMSCs.
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Affiliation(s)
- Xiao Zheng
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.,Department of Oral Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.,Department of Pediatric Dentistry, Shenzhen Stomatology Hospital (Pingshan), Southern Medical University, Shenzhen, Guangdong, China
| | - Shuaiqi Gan
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.,Department of Oral Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Cheng Su
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.,Department of Oral Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Zheng Zheng
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.,Department of Oral Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Yihan Liao
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.,Department of Oral Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Jingjing Shao
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.,Department of Oral Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Zhimin Zhu
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.,Department of Oral Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Wenchuan Chen
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.,Department of Oral Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
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Protective Effect of Human Umbilical Cord Mesenchymal Stem Cells in Glucocorticoid-induced Osteonecrosis of Femoral Head. Curr Med Sci 2021; 41:909-915. [PMID: 34689292 DOI: 10.1007/s11596-021-2439-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Accepted: 04/15/2021] [Indexed: 10/20/2022]
Abstract
OBJECTIVE To evaluate the effect of human umbilical cord mesenchymal stem cells (hUC-MSCs) on preventing rats from glucocorticoid-induced osteonecrosis of femoral head (GCONFH) in the early stage in vivo and to investigate the possible mechanism of hUC-MSCs in regulating the balance of osteogenesis and adipogenesis. METHODS All rats were randomly divided into 3 groups: control group (C group), model group (M group), and intervention group (I group). The model of GC-ONFH was developed by a sequential administration of lipopolysaccharide and methylprednisolone. The rats in the I group were treated with caudal vein injection of hUC-MSCs. Six weeks later, the blood samples were obtained to measure the activity of alkaline phosphatase (ALP) and the content of triglyceride (TG) in serum, and the femoral heads were harvested and observed by hematoxylin-eosin staining, Micro-CT, Western blot and real-time quantitative polymerase chain reaction. RESULTS After intervention of hUC-MSCs, the necrosis rate of femoral head decreased from 83% (10/12) to 33% (4/12), the rate of empty bone lacuna was significantly decreased, the activity of ALP increased significantly, the content of TG decreased significantly, the bone density increased obviously, the expression of RUNX2 and Col I increased significantly and the expression of PPARγ decreased significantly. CONCLUSION These results revealed that caudal vein injection of hUC-MSCs can effectively reduce the incidence of GC-ONFH in rats by increasing ALP activity and reducing TG content in serum, increasing bone mineral density, promoting the expression of RUNX2 and Col I, and inhibiting the expression of PPARγ.
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Ren X, Wang Q, Liu C, Zhao Q, Zheng J, Tian K, Xu H, Mu Y. Osteogenic ability using porous hydroxyapatite scaffold-based delivery of human placenta-derived mesenchymal stem cells. Exp Ther Med 2021; 22:1091. [PMID: 34504545 PMCID: PMC8383769 DOI: 10.3892/etm.2021.10525] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Accepted: 06/11/2021] [Indexed: 12/18/2022] Open
Abstract
Previous preliminary studies have suggested that hydroxyapatite with a grooved structure (HAG) scaffold has good osteogenic potential. This type of scaffold may aid osteogenesis during the repair of large maxillofacial bony defects. The ectopic osteogenic effect and underlying mechanism were further studied using porous HAG scaffold-based delivery of human placenta-derived mesenchymal stem cells (hPMSCs). A total of 18 dogs were randomly allocated into a HAG scaffold group and a HAG scaffold-based hPMSC (HAG/hPMSC) group, and three scaffolds were implanted into the dorsal muscle of each dog. Samples were taken for subsequent analysis and tested 4, 8 and 12 weeks following heterotopic implantation. H&E staining was used to study the osteogenic effect in dog dorsal muscles, and RNA sequencing (RNA-seq) was used for exploring the underlying osteogenic mechanism. The osteogenic ability and effector of the HAG/hPMSC group were significantly greater than those of the HAG scaffold group at 4 weeks after implantation. After 12 weeks, a mature bone plate structure was seen in the HAG/hPMSC group. RNA-seq demonstrated that various osteogenesis-related pathways participated at different stages of metabolism, and that the expression of collagen-1 and runt-related transcription factor 2 increased with implantation time. The present study preliminarily focused on the ectopic osteogenic effect of the porous HAG scaffold-based delivery of hPMSCs in vivo, which may be helpful for the improved application of HAG scaffolds in the future.
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Affiliation(s)
- Xiaohua Ren
- Stomatology Department, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, P.R. China
| | - Qingwei Wang
- Institute of Chengdu Biology and Sichuan Translational Medicine Hospital, Chinese Academy of Sciences, Chengdu, Sichuan 610041, P.R. China
| | - Chunhui Liu
- Stomatology Department, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, P.R. China
| | - Qian Zhao
- Shuangliu Hospital of Traditional Chinese Medicine, Chengdu, Sichuan 610000, P.R. China
| | - Jiajun Zheng
- Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Kun Tian
- Stomatology Department, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, P.R. China
| | - Huijuan Xu
- Institute of Chengdu Biology and Sichuan Translational Medicine Hospital, Chinese Academy of Sciences, Chengdu, Sichuan 610041, P.R. China.,The University of Chinese Academy of Sciences, Beijing 100039, P.R. China
| | - Yandong Mu
- Stomatology Department, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, P.R. China
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Mollentze J, Durandt C, Pepper MS. An In Vitro and In Vivo Comparison of Osteogenic Differentiation of Human Mesenchymal Stromal/Stem Cells. Stem Cells Int 2021; 2021:9919361. [PMID: 34539793 PMCID: PMC8443361 DOI: 10.1155/2021/9919361] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 07/23/2021] [Accepted: 08/20/2021] [Indexed: 12/11/2022] Open
Abstract
The use of stem cells in regenerative medicine, including tissue engineering and transplantation, has generated a great deal of enthusiasm. Mesenchymal stromal/stem cells (MSCs) can be isolated from various tissues, most commonly, bone marrow but more recently adipose tissue, dental pulp, and Wharton's jelly, to name a few. MSCs display varying phenotypic profiles and osteogenic differentiating capacity depending and their site of origin. MSCs have been successfully differentiated into osteoblasts both in vitro an in vivo but discrepancies exist when the two are compared: what happens in vitro does not necessarily happen in vivo, and it is therefore important to understand why these differences occur. The osteogenic process is a complex network of transcription factors, stimulators, inhibitors, proteins, etc., and in vivo experiments are helpful in evaluating the various aspects of this osteogenic process without distractions and confounding variables. With that in mind, the results of in vitro experiments need to be carefully considered and interpreted with caution as they do not perfectly replicate the conditions found within living organisms. This is where in vivo experiments help us better understand interactions that might occur in the osteogenic process that cannot be replicated in vitro. Potentially, these differences could also be exploited to develop an optimal MSC cell therapeutic product that can be used for bone disorders. There are many bone disorders, most of which cause a great deal of discomfort. Clinically acceptable protocols could be developed in which MSCs are used to aid in bone regeneration providing relief for patients with chronic pain. The aim of this review is to examine the differences between studies conducted in vitro and in vivo with regard to the osteogenic process to better define the gaps in current osteogenic research. By better understanding osteogenic differentiation, we can better define treatment strategies for various bone disorders.
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Affiliation(s)
- Jamie Mollentze
- Institute for Cellular and Molecular Medicine, Department of Immunology; SAMRC Extramural Unit for Stem Cell Research and Therapy, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa
| | - Chrisna Durandt
- Institute for Cellular and Molecular Medicine, Department of Immunology; SAMRC Extramural Unit for Stem Cell Research and Therapy, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa
| | - Michael S. Pepper
- Institute for Cellular and Molecular Medicine, Department of Immunology; SAMRC Extramural Unit for Stem Cell Research and Therapy, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa
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Geng X, Zou Y, Li S, Qi R, Jing C, Ding X, Li J, Yu H. Electroacupuncture promotes the recovery of rats with spinal cord injury by suppressing the Notch signaling pathway via the H19/EZH2 axis. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:844. [PMID: 34164478 PMCID: PMC8184438 DOI: 10.21037/atm-21-1526] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Background Spinal cord injury (SCI) is a life-changing event with an extremely poor prognosis. In our preliminary studies, electroacupuncture (EA) was found to promote the repair of SCI, which was closely related to the Notch signaling pathway. Therefore, in the present study, we hypothesized that EA protects against SCI by inhibiting the Notch signaling pathway and sought to investigate the underlying molecular mechanisms. Methods Rat and cell models of SCI were established. The expression of long non-coding RNA H19 was measured by real-time quantitative polymerase chain reaction. The expression levels of EZH2, Notch1, Notch3, Notch4, Hes1, and PS1 protein were measured by western blot. Cell apoptosis and viability were analyzed using flow cytometry and Cell Counting Kit-8 assays, respectively. The expressions of glial fibrillary acidic protein (GFAP) and nestin were detected by immunofluorescence staining. Results The expressions of H19, EZH2, and GFAP were significantly increased after SCI but were inhibited by EA; in contrast, nestin expression was significantly decreased by SCI but was restored by EA. Moreover, oxygen-glucose deprivation (OGD) treatment elevated the expression of H19, EZH2, and Notch-related factors as well as apoptosis in PC-12 cells, while suppressing cell viability. Suppressing H19 alleviated the effects of OGD on cell viability and apoptosis, and inhibited the expression of EZH2 and Notch-related factors expression; these effects were reversed by EZH2 overexpression. Finally, EA promoted the recovery of SCI rats and neural stem cell (NSC) proliferation by inhibiting the Notch signaling pathway, which was reversed by H19 overexpression. Conclusions Our results demonstrated that EA promotes the recovery of SCI rats and increases the proliferation and differentiation of NSCs by suppressing the Notch signaling pathway via modulating the H19/EZH2 axis.
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Affiliation(s)
- Xin Geng
- Second Department of Neurosurgery, First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Yanghong Zou
- Second Department of Neurosurgery, First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Shipeng Li
- Second Department of Neurosurgery, First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Renli Qi
- Second Department of Neurosurgery, First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Cong Jing
- Second Department of Neurosurgery, First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Xiangqian Ding
- Second Department of Neurosurgery, First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Jinghui Li
- Second Department of Neurosurgery, First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Hualin Yu
- Second Department of Neurosurgery, First Affiliated Hospital of Kunming Medical University, Kunming, China
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Wu Z, Zhang Y, Yang Z, Zhu Y, Xie Y, Zhou F, Cai L. Elevation of miR-302b prevents multiple myeloma cell growth and bone destruction by blocking DKK1 secretion. Cancer Cell Int 2021; 21:187. [PMID: 33789678 PMCID: PMC8011228 DOI: 10.1186/s12935-021-01887-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 03/22/2021] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Myeloma bone disease (MBD) is a severe complication of multiple myeloma (MM) mainly due to an imbalance between enhanced osteoclast activity and reduced osteoblast function. Previous studies have demonstrated that miRNAs play a vital role in the osteogenic differentiation of mesenchymal stromal cells (MSCs) in MM. However, the value of miR‑302b in MBD remains to be further elucidated. The aim of this study is to explore the role of miR‑302b in the regulation of MBD osteogenic differentiation and evaluate the potential of a new therapeutic strategy for the clinical treatment of MBD. METHOD Our previous research demonstrated that MiR-302b belongs to the miR-302 cluster and is able to inhibit tumor growth and osteolysis in an orthotopic osteosarcoma xenograft tumor mouse model. In this study, we first transfected miR-302b mimics, miR-302b inhibitor, and miR-302b NC into MM1.S and RPMI8226 MM cells to detect the correlation between miR-302b expression in the pathological specimens and the clinicopathological features by qPCR, the target correlation between miR-302b and DKK1 by immunohistochemistry, qPCR and Western blot, and the correlation between miR-302b and the Wnt/β-catenin signaling pathway by Western blot. The effect of miR-302b on osteoblastogenesis was also studied in a subperiosteal tumorigenesis model of NOD/SCID nude mice. RESULTS We found that increased miR-302b suppressed cell proliferation and induced cell apoptosis in RPMI 8226 and MM1.S cells. TargetScan online bioinformatic analysis predicted that miR-302b is able to bind to 3'UTR of DKK1 mRNA. Target binding of miR-302b to DKK1 was demonstrated by dual-luciferase reporter assay, qPCR, Western blot and immunohistochemistry, indicating that miR-302b is able to degrade DKK1 in RPMI 8226 and MM1.S cells. The model of co-culturing MM cells with preosteoblast MC3T3-E1 cells showed that miR-302b inhibits MM-induced suppression of osteoblast differentiation. Western blotting showed that miR-302b promotes the Wnt/β-catenin signaling pathway in MM cells. Micro-CT and immunohistochemistry results showed that miR-302b suppresses myeloma bone destruction in vivo. CONCLUSION miR-302b is able to target DKK1 and promote the Wnt/β-catenin signaling pathway in MM.
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Affiliation(s)
- Zheyu Wu
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, China
| | - Yufeng Zhang
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, China
| | - Zhiqiang Yang
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, China
| | - Yufan Zhu
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, China
| | - Yuanlong Xie
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, China
| | - Fuling Zhou
- Department of Hematology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, China
| | - Lin Cai
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, China.
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Arjmand B, Sarvari M, Alavi-Moghadam S, Payab M, Goodarzi P, Gilany K, Mehrdad N, Larijani B. Prospect of Stem Cell Therapy and Regenerative Medicine in Osteoporosis. Front Endocrinol (Lausanne) 2020; 11:430. [PMID: 32719657 PMCID: PMC7347755 DOI: 10.3389/fendo.2020.00430] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Accepted: 06/01/2020] [Indexed: 12/13/2022] Open
Abstract
The field of cell therapy and regenerative medicine can hold the promise of restoring normal tissues structure and function. Additionally, the main targets of stem cell-based therapies are chronic diseases and lifelong disabilities without definite cures such as osteoporosis. Osteoporosis as one of the important causes of morbidity in older men and post-menopausal women is characterized by reduced bone quantity or skeletal tissue atrophy that leads to an increased risk of osteoporotic fractures. The common therapeutic methods for osteoporosis only can prevent the loss of bone mass and recover the bone partially. Nevertheless, stem cell-based therapy is considered as a new approach to regenerate the bone tissue. Herein, mesenchymal stem cells as pivotal candidates for regenerative medicine purposes especially bone regeneration are the most common type of cells with anti-inflammatory, immune-privileged potential, and less ethical concerns than other types of stem cells which are investigated in osteoporosis. Based on several findings, the mesenchymal stem cells effectiveness near to a great extent depends on their secretory function. Indeed, they can be involved in the establishment of normal bone remodeling via initiation of specific molecular signaling pathways. Accordingly, the aim herein was to review the effects of stem cell-based therapies in osteoporosis.
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Affiliation(s)
- Babak Arjmand
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- Metabolomics and Genomics Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Masoumeh Sarvari
- Metabolomics and Genomics Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Sepideh Alavi-Moghadam
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Moloud Payab
- Obesity and Eating Habits Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Parisa Goodarzi
- Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Kambiz Gilany
- Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium
- Integrative Oncology Department, Breast Cancer Research Center, Motamed Cancer Institute, Academic Center for Education, Culture and Research (ACER), Tehran, Iran
- Reproductive Immunology Research Center, Avicenna Research Institute, Academic Center for Education, Culture and Research (ACER), Tehran, Iran
| | - Neda Mehrdad
- Elderly Health Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Bagher Larijani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
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11
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Macías I, Alcorta-Sevillano N, Rodríguez CI, Infante A. Osteoporosis and the Potential of Cell-Based Therapeutic Strategies. Int J Mol Sci 2020; 21:ijms21051653. [PMID: 32121265 PMCID: PMC7084428 DOI: 10.3390/ijms21051653] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 02/24/2020] [Accepted: 02/25/2020] [Indexed: 12/14/2022] Open
Abstract
Osteoporosis, the most common chronic metabolic bone disease, is characterized by low bone mass and increased bone fragility. Nowadays more than 200 million individuals are suffering from osteoporosis and still the number of affected people is dramatically increasing due to an aging population and longer life, representing a major public health problem. Current osteoporosis treatments are mainly designed to decrease bone resorption, presenting serious adverse effects that limit their safety for long-term use. Numerous studies with mesenchymal stem cells (MSCs) have helped to increase the knowledge regarding the mechanisms that underlie the progression of osteoporosis. Emerging clinical and molecular evidence suggests that inflammation exerts a significant influence on bone turnover, thereby on osteoporosis. In this regard, MSCs have proven to possess broad immunoregulatory capabilities, modulating both adaptive and innate immunity. Here, we will discuss the role that MSCs play in the etiopathology of osteoporosis and their potential use for the treatment of this disease.
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12
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He S, Yang S, Zhang Y, Li X, Gao D, Zhong Y, Cao L, Ma H, Liu Y, Li G, Peng S, Shuai C. LncRNA ODIR1 inhibits osteogenic differentiation of hUC-MSCs through the FBXO25/H2BK120ub/H3K4me3/OSX axis. Cell Death Dis 2019; 10:947. [PMID: 31827076 PMCID: PMC6906393 DOI: 10.1038/s41419-019-2148-2] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 11/01/2019] [Accepted: 11/11/2019] [Indexed: 01/26/2023]
Abstract
Long noncoding RNAs (lncRNAs) have been demonstrated to be important regulators during the osteogenic differentiation of mesenchymal stem cells (MSCs). We analyzed the lncRNA expression profile during osteogenic differentiation of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) and identified a significantly downregulated lncRNA RP11-527N22.2, named osteogenic differentiation inhibitory lncRNA 1, ODIR1. In hUC-MSCs, ODIR1 knockdown significantly promoted osteogenic differentiation, whereas overexpression inhibited osteogenic differentiation in vitro and in vivo. Mechanistically, ODIR1 interacts with F-box protein 25 (FBXO25) and facilitates the proteasome-dependent degradation of FBXO25 by recruiting Cullin 3 (CUL3). FBXO25 increases the mono-ubiquitination of H2BK120 (H2BK120ub) which subsequently promotes the trimethylation of H3K4 (H3K4me3). Both H2BK120ub and H3K4me3 form a loose chromatin structure, inducing the transcription of the key transcription factor osterix (OSX) and increasing the expression of the downstream osteoblast markers, osteocalcin (OCN), osteopontin (OPN), and alkaline phosphatase (ALP). In summary, ODIR1 acts as a key negative regulator during the osteogenic differentiation of hUC-MSCs through the FBXO25/H2BK120ub/H3K4me3/OSX axis, which may provide a novel understanding of lncRNAs that regulate the osteogenesis of MSCs and a potential therapeutic strategy for the regeneration of bone defects.
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Affiliation(s)
- Shiwei He
- NHC Key Laboratory of Carcinogenesis, Hunan Provincial Tumor Hospital, Central South University, Changsha, 410013, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, 410078, China
- Hunan Key Laboratory of Non-resolving Inflammation and Cancer, Disease Genome Research Center, the Third Xiangya Hospital, Central South University, Changsha, 410013, China
| | - Sheng Yang
- Department of Obstetrics and Gynecology, General Hospital, Shenzhen University, Shenzhen, 518053, China
| | - Yanru Zhang
- NHC Key Laboratory of Carcinogenesis, Hunan Provincial Tumor Hospital, Central South University, Changsha, 410013, China
| | - Xiaoling Li
- NHC Key Laboratory of Carcinogenesis, Hunan Provincial Tumor Hospital, Central South University, Changsha, 410013, China
| | - Dan Gao
- NHC Key Laboratory of Carcinogenesis, Hunan Provincial Tumor Hospital, Central South University, Changsha, 410013, China
| | - Yancheng Zhong
- NHC Key Laboratory of Carcinogenesis, Hunan Provincial Tumor Hospital, Central South University, Changsha, 410013, China
| | - Lihua Cao
- NHC Key Laboratory of Carcinogenesis, Hunan Provincial Tumor Hospital, Central South University, Changsha, 410013, China
| | - Haotian Ma
- NHC Key Laboratory of Carcinogenesis, Hunan Provincial Tumor Hospital, Central South University, Changsha, 410013, China
| | - Ying Liu
- NHC Key Laboratory of Carcinogenesis, Hunan Provincial Tumor Hospital, Central South University, Changsha, 410013, China
| | - Guiyuan Li
- NHC Key Laboratory of Carcinogenesis, Hunan Provincial Tumor Hospital, Central South University, Changsha, 410013, China
| | - Shuping Peng
- NHC Key Laboratory of Carcinogenesis, Hunan Provincial Tumor Hospital, Central South University, Changsha, 410013, China.
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, 410078, China.
- Hunan Key Laboratory of Non-resolving Inflammation and Cancer, Disease Genome Research Center, the Third Xiangya Hospital, Central South University, Changsha, 410013, China.
| | - Cijun Shuai
- Jiangxi University of Science and Technology, Ganzhou, 341000, China.
- State Key Laboratory of High Performance Complex Manufacturing, Central South University, Changsha, 410083, China.
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13
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Fan FY, Deng R, Lai SH, Wen Q, Zeng Y, Gao L, Liu Y, Kong P, Zhong J, Su Y, Zhang X. Inhibition of microRNA-221-5p induces osteogenic differentiation by directly targeting smad3 in myeloma bone disease mesenchymal stem cells. Oncol Lett 2019; 18:6536-6544. [PMID: 31788114 PMCID: PMC6865756 DOI: 10.3892/ol.2019.10992] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Accepted: 06/14/2019] [Indexed: 01/08/2023] Open
Abstract
Myeloma bone disease (MBD) is one of the clinical features of multiple myeloma, which contributes to the attenuation of osteoblast function. Bone marrow mesenchymal stem cells exhibit a high potential for differentiation into osteoblasts. A number of studies have reported that microRNAs (miRs) serve a vital role in mesenchymal stem cell (MSC) osteogenesis; however, the role of miR-221-5p in the osteogenic differentiation of MBD-MSCs remains unclear. The present study revealed that the osteogenic differentiation capacity of MBD-MSCs was reduced compared with that of normal (N)-MSCs. Further experiments demonstrated that miR-221-5p expression was downregulated in N-MSCs following osteoblast induction while no obvious alterations in expression levels were observed in MBD-MSCs. The inhibition of miR-221-5p promoted the osteogenic differentiation of MBD-MSCs. Bioinformatics, luciferase reporter assays, reverse transcription-quantitative PCR and western blotting assays indicated that smad family member 3 (smad3) was a direct target of miR-221-5p in MBD-MSCs. A negative association was identified between the expression levels of smad3 and miR-221-5p. Investigations of the molecular mechanism indicated that suppressed miR-221-5p could regulate the osteogenic differentiation of MBD-MSCs by upregulating smad3 expression. It was also identified that the PI3K/AKT/mTOR signaling pathway was activated following miR-221-5p inhibition, and this increased the osteogenic differentiation capacity of MBD-MSCs. The present study may improve the understanding regarding the role of miR-221-5p in the regulation of osteogenic differentiation, and may contribute to the development of a novel therapy for MBD.
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Affiliation(s)
- Fang-Yi Fan
- Department of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, Sichuan 400037, P.R. China.,Department of Hematology and Hematopoetic Stem Cell Transplantation Centre, The General Hospital of Western Theater Command, Chengdu, Sichuan 610083, P.R. China
| | - Rui Deng
- Department of Hematology and Hematopoetic Stem Cell Transplantation Centre, The General Hospital of Western Theater Command, Chengdu, Sichuan 610083, P.R. China
| | - Si-Han Lai
- Department of Hematology and Hematopoetic Stem Cell Transplantation Centre, The General Hospital of Western Theater Command, Chengdu, Sichuan 610083, P.R. China
| | - Qin Wen
- Department of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, Sichuan 400037, P.R. China
| | - Yunjing Zeng
- Department of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, Sichuan 400037, P.R. China
| | - Lei Gao
- Department of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, Sichuan 400037, P.R. China
| | - Yao Liu
- Department of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, Sichuan 400037, P.R. China
| | - Peiyan Kong
- Department of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, Sichuan 400037, P.R. China
| | - Jiangfan Zhong
- Department of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, Sichuan 400037, P.R. China
| | - Yi Su
- Department of Hematology and Hematopoetic Stem Cell Transplantation Centre, The General Hospital of Western Theater Command, Chengdu, Sichuan 610083, P.R. China
| | - Xi Zhang
- Department of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, Sichuan 400037, P.R. China
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14
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Kargozar S, Mozafari M, Hamzehlou S, Brouki Milan P, Kim HW, Baino F. Bone Tissue Engineering Using Human Cells: A Comprehensive Review on Recent Trends, Current Prospects, and Recommendations. APPLIED SCIENCES 2019; 9:174. [DOI: 10.3390/app9010174] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The use of proper cells for bone tissue engineering remains a major challenge worldwide. Cells play a pivotal role in the repair and regeneration of the bone tissue in vitro and in vivo. Currently, a large number of differentiated (somatic) and undifferentiated (stem) cells have been used for bone reconstruction alone or in combination with different biomaterials and constructs (e.g., scaffolds). Although the results of the cell transplantation without any supporting or adjuvant material have been very effective with regard to bone healing. Recent advances in bone scaffolding are now becoming new players affecting the osteogenic potential of cells. In the present study, we have critically reviewed all the currently used cell sources for bone reconstruction and discussed the new horizons that are opening up in the context of cell-based bone tissue engineering strategies.
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Affiliation(s)
- Saeid Kargozar
- Department of Modern Sciences and Technologies, School of Medicine, Mashhad University of Medical Sciences, Mashhad 917794-8564, Iran
| | - Masoud Mozafari
- Bioengineering Research Group, Nanotechnology and Advanced Materials Department, Materials and Energy Research Center (MERC), Tehran 14155-4777, Iran
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Tissue Engineering & Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences (IUMS), Tehran 144961-4535, Iran
| | - Sepideh Hamzehlou
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran 14155-6447, Iran
- Medical Genetics Network (MeGeNe), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Peiman Brouki Milan
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Tissue Engineering & Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences (IUMS), Tehran 144961-4535, Iran
| | - Hae-Won Kim
- Department of Biomaterials Science, School of Dentistry, Dankook University, Cheonan 31116, Korea
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan 31116, Korea
- Department of Nanobiomedical Science & BK21 PLUS NBM Global Research Center for Regenerative Medicine Research Center, Dankook University, Cheonan 31116, Korea
| | - Francesco Baino
- Institute of Materials Physics and Engineering, Applied Science and Technology Department, Politecnico di Torino, Corso Duca degli Abruzzi 24, 10129 Torino, Italy
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15
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Hendrijantini N, Hartono P. Phenotype Characteristics and Osteogenic Differentiation Potential of Human Mesenchymal Stem Cells Derived from Amnion Membrane (HAMSCs) and Umbilical Cord (HUC-MSCs). Acta Inform Med 2019; 27:72-77. [PMID: 31452562 PMCID: PMC6688306 DOI: 10.5455/aim.2019.27.72-77] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Introduction: Human amnion membrane mesenchymal stem cells (hAMSCs) and human umbilical cord mesenchymal stem cells (hUC-MSCs) are potential, non invasive sources of stem cells used for bone tissue engineering. Phenotyping characterization is an extremely important consideration in the choice of the appropriate passage in order to maximize its osteogenic differentiation potential. Aim: To explore phenotype characteristics and compare osteogenic differentiation potential of hAMSCs and hUC-MSCs. Method: Isolation and culture were performed on hAMSCs and hUC-MSCs from a healthy woman in her 38th weeks of pregnancy. CD90, CD105 and CD73 phenotype characterization was done in passage 4-7. An osteogenic differentiation examination of hAMSCs and hUC-MSCs with Alizarin red staining and RUNX2 expression was performed in the passage that had appropriate expressions of phenotype characteristics. Results: The expression of CD90 hUC-MSCs was higher than that of hAMSCs in all passages. CD105 hUC-MSCs was higher in passage 4-6, while CD105 hAMSCs was equal to that of hUC-MSCs in passage 7. CD73 hUC-MSCs was higher than hAMSCs in passage 4 and 5, while in passage 6 and 7 hAMSCs was higher than hUC-MSCs. There was a decrease in the number of CD90, CD105 and CD73 on hAMSCs and hUC-MSCs in passage 5, then determined as appropriate passage. Alizarin red staining examination showed calcium deposition and revealed no significant difference, but RUNX2 expression of hUC-MSCs was significantly higher than that for hAMSCs. Conclusion: Both hAMSCs and hUC-MSCs had phenotype characteristics of mesenchymal stem cell and showed ostegenic differentiation potential.
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Affiliation(s)
- Nike Hendrijantini
- Department of Prosthodontic, Faculty of Dental Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Poedjo Hartono
- Department of Obstetrics and Gynaecology, Dr. Soetomo General Hospital, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
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16
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Aghebati‐Maleki L, Dolati S, Zandi R, Fotouhi A, Ahmadi M, Aghebati A, Nouri M, Kazem Shakouri S, Yousefi M. Prospect of mesenchymal stem cells in therapy of osteoporosis: A review. J Cell Physiol 2018; 234:8570-8578. [PMID: 30488448 DOI: 10.1002/jcp.27833] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2018] [Accepted: 11/07/2018] [Indexed: 12/18/2022]
Affiliation(s)
- Leili Aghebati‐Maleki
- Immunology Research Center, Tabriz University of Medical Sciences Tabriz Iran
- Department of Immunology Faculty of Medicine, Tabriz University of Medical Sciences Tabriz Iran
| | - Sanam Dolati
- Aging Research Institute, Tabriz University of Medical Sciences Tabriz Iran
- Student Research Committee, Tabriz University of Medical Sciences Tabriz Iran
| | - Reza Zandi
- Department of Orthopedic Surgery Faculty of Medicine, Shahid Beheshti University of Medical Sciences Tehran Iran
| | - Ali Fotouhi
- Department of Orthopedic Surgery Faculty of Medicine, Shahid Beheshti University of Medical Sciences Tehran Iran
| | - Majid Ahmadi
- Department of Reproductive Biology Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences Tabriz Iran
| | - Ali Aghebati
- Immunology Research Center, Tabriz University of Medical Sciences Tabriz Iran
| | - Mohammad Nouri
- Department of Reproductive Biology Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences Tabriz Iran
| | - Seyed Kazem Shakouri
- Physical Medicine and Rehabilitation Research Centre, Tabriz University of Medical Sciences Tabriz Iran
| | - Mehdi Yousefi
- Stem Cell Research Center, Tabriz University of Medical Sciences Tabriz Iran
- Department of Immunology Faculty of Medicine, Tabriz University of Medical Sciences Tabriz Iran
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17
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Osteogenic Potential of Human Umbilical Cord Mesenchymal Stem Cells on Coralline Hydroxyapatite/Calcium Carbonate Microparticles. Stem Cells Int 2018; 2018:4258613. [PMID: 30254682 PMCID: PMC6145045 DOI: 10.1155/2018/4258613] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2018] [Accepted: 05/16/2018] [Indexed: 01/15/2023] Open
Abstract
Coralline hydroxyapatite/calcium carbonate (CHACC) is a biodegradable and osteoconductive bone graft material with promising clinical performance. CHACC has been shown to support proliferation and osteogenic differentiation of human bone marrow mesenchymal stem cells (MSCs) in vitro and demonstrated to work as a functional scaffold for bone formation in vivo. Umbilical cord matrix is a more accessible and abundant tissue source of MSCs, but its osteogenic capacity in comparison to human bone marrow when cultured on CHACC has not yet been demonstrated. In this study, we assessed the osteogenic differentiation capacity of human MSCs, isolated from bone marrow and umbilical cord matrix and characterised by flow cytometry, when cultured on 200–300 μm CHACC granules. The 3D cultures were characterised by brightfield and scanning electron microscopy (SEM). Osteogenic potential was assessed by immunocytochemistry and qPCR for key markers of bone differentiation (alkaline phosphatase, runx2, type I collagen, and osteocalcin). By day 1, the MSCs had enveloped the surface of the CHACC granules to form organoids, and by day 7, cells had proliferated to bridge nearby organoids. Extracellular matrix deposition and osteogenic differentiation were demonstrated by MSCs from both tissue sources at day 21. However, MSCs from bone marrow demonstrated superior osteogenic differentiation capability compared to those from umbilical cord matrix. In conclusion, it is possible to culture and induce osteogenic differentiation of umbilical cord matrix MSCs on CHACC. Further research is required to optimise the osteogenicity of umbilical cord matrix MSCs to release their full potential as a readily available, accessible, and abundant tissue source for bone tissue engineering.
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18
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Al Jofi FE, Ma T, Guo D, Schneider MP, Shu Y, Xu HHK, Schneider A. Functional organic cation transporters mediate osteogenic response to metformin in human umbilical cord mesenchymal stromal cells. Cytotherapy 2018; 20:650-659. [PMID: 29555409 DOI: 10.1016/j.jcyt.2018.02.369] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Revised: 01/28/2018] [Accepted: 02/11/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Compelling evidence indicates that metformin, a low-cost and safe orally administered biguanide prescribed to millions of type 2 diabetics worldwide, induces the osteoblastic differentiation of mesenchymal stromal cells (MSCs) through the 5' adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway. As a highly hydrophilic cationic compound, metformin uptake is facilitated by cell membrane organic cation transporters (OCTs) of the solute carrier 22A gene family. We hypothesized that to effectively enhance osteogenic differentiation, and ultimately bone regeneration, metformin must gain access into functional OCT-expressing MSCs. METHODS Data was obtained through immunoblotting, cellular uptake, mineralization and gene expression assays. RESULTS We demonstrate for the first time that functional OCTs are expressed in human-derived MSCs from umbilical cord Wharton's jelly, an inexhaustible source of nonembryonic MSCs with proven osteogenic potential. A clinically relevant concentration of metformin led to AMPK activation, enhanced mineralized nodule formation and increased expression of the osteogenic transcription factor Runt-related transcription factor 2 (RUNX2). Indeed, targeting OCT function through pharmacological and genetic approaches markedly blunted these responses. CONCLUSIONS Our findings indicate that functional OCT expression in UC-MSCs is a biological prerequisite that facilitates the intracellular uptake of metformin to induce an osteogenic effect. Future pre-clinical studies are warranted to investigate whether the expression of functional OCTs may serve as a potential biomarker to predict osteogenic responses to metformin.
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Affiliation(s)
- Faisal E Al Jofi
- Department of Oncology and Diagnostic Sciences, School of Dentistry, University of Maryland, Baltimore, Maryland, USA; Department of Preventive Dental Science, Division of Periodontics, Imam Abdulrahman Bin Faisal University, College of Dentistry, Dammam, Saudi Arabia
| | - Tao Ma
- Department of Oncology and Diagnostic Sciences, School of Dentistry, University of Maryland, Baltimore, Maryland, USA
| | - Dong Guo
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland, USA
| | - Monica P Schneider
- Department of Orthodontics and Pediatric Dentistry, School of Dentistry, University of Maryland, Baltimore, Maryland, USA
| | - Yan Shu
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland, USA; Greenebaum Comprehensive Cancer Center, Program in Oncology, School of Medicine, University of Maryland, Baltimore, Maryland, USA
| | - Hockin H K Xu
- Greenebaum Comprehensive Cancer Center, Program in Oncology, School of Medicine, University of Maryland, Baltimore, Maryland, USA; Biomaterials and Tissue Engineering Division, Department of Advanced Oral Sciences and Therapeutics, School of Dentistry, University of Maryland, Baltimore, Maryland, USA; Center for Stem Cell Biology and Regenerative Medicine, School of Medicine, University of Maryland, Baltimore, Maryland, USA
| | - Abraham Schneider
- Department of Oncology and Diagnostic Sciences, School of Dentistry, University of Maryland, Baltimore, Maryland, USA; Greenebaum Comprehensive Cancer Center, Program in Oncology, School of Medicine, University of Maryland, Baltimore, Maryland, USA.
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19
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Kargozar S, Mozafari M, Hashemian SJ, Brouki Milan P, Hamzehlou S, Soleimani M, Joghataei MT, Gholipourmalekabadi M, Korourian A, Mousavizadeh K, Seifalian AM. Osteogenic potential of stem cells-seeded bioactive nanocomposite scaffolds: A comparative study between human mesenchymal stem cells derived from bone, umbilical cord Wharton's jelly, and adipose tissue. J Biomed Mater Res B Appl Biomater 2018; 106:61-72. [PMID: 27862947 DOI: 10.1002/jbm.b.33814] [Citation(s) in RCA: 74] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2016] [Revised: 10/07/2016] [Accepted: 10/27/2016] [Indexed: 02/02/2023]
Abstract
Bone regeneration is considered as an unmet clinical need, the aim of this study is to investigate the osteogenic potential of three different mesenchymal stem cells (MSCs) derived from human bone marrow (BM-MSCs), umbilical cord Wharton's jelly (UC-MSCs), and adipose (AD-MSCs) seeded on a recently developed nanocomposite scaffold (bioactive glass/gelatin) implanted in rat animal models with critical size calvarial defects. In this study, after isolation, culture, and characterization, the MSCs were expanded and seeded on the scaffolds for in vitro and in vivo studies. The adhesion, proliferation, and viability of the cells on the scaffolds evaluated in vitro, showed that the scaffolds were biocompatible for further examinations. In order to evaluate the scaffolds in vivo, rat animal models with critical size calvarial defects were randomly categorized in four groups and treated with the scaffolds. The animals were sacrificed at the time points of 4 and 12 weeks of post-implantation, bone healing process were investigated. The histological and immunohistological observations showed (p < 0.01) higher osteogenesis capacity in the group treated with BM-MSCs/scaffolds compared to the other groups. However, the formation of new angiogenesis was evidently higher in the defects filled with UC-MSCs/scaffolds. This preliminary study provides promising data for further clinical trials. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 61-72, 2018.
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Affiliation(s)
- Saeid Kargozar
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
- National Cell Bank, Pasteur Institute of Iran, Tehran, Iran
| | - Masoud Mozafari
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
- Cellular and Molecular Research Center (CMRC), Iran University of Medical Sciences, Tehran, Iran
| | - Seyed Jafar Hashemian
- Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Peiman Brouki Milan
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
- Cellular and Molecular Research Center (CMRC), Iran University of Medical Sciences, Tehran, Iran
| | - Sepideh Hamzehlou
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mansooreh Soleimani
- Cellular and Molecular Research Center (CMRC), Iran University of Medical Sciences, Tehran, Iran
- Department of Anatomy, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Taghi Joghataei
- Cellular and Molecular Research Center (CMRC), Iran University of Medical Sciences, Tehran, Iran
- Department of Anatomy, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mazaher Gholipourmalekabadi
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
- Cellular and Molecular Biology Research Centre, Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Alireza Korourian
- Cellular and Molecular Research Center (CMRC), Iran University of Medical Sciences, Tehran, Iran
| | - Kazem Mousavizadeh
- Cellular and Molecular Research Center (CMRC), Iran University of Medical Sciences, Tehran, Iran
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Alexander M Seifalian
- Division of Surgery and Interventional Science, UCL Centre for Nanotechnology and Regenerative Medicine, University College London, London, UK
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20
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Lam J, Lee EJ, Clark EC, Mikos AG. Honing Cell and Tissue Culture Conditions for Bone and Cartilage Tissue Engineering. Cold Spring Harb Perspect Med 2017; 7:a025734. [PMID: 28348176 PMCID: PMC5710100 DOI: 10.1101/cshperspect.a025734] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
An avenue of tremendous interest and need in health care encompasses the regeneration of bone and cartilage. Over the years, numerous tissue engineering strategies have contributed substantial progress toward the realization of clinically relevant therapies. Cell and tissue culture protocols, however, show many variations that make experimental results among different publications challenging to compare. This collection surveys prevalent cell sources, soluble factors, culture medium formulations, environmental factors, and genetic modification approaches in the literature. The intent of consolidating this information is to provide a starting resource for scientists considering how to optimize the parameters for cell differentiation and tissue culture procedures within the context of bone and cartilage tissue engineering.
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Affiliation(s)
- Johnny Lam
- Department of Bioengineering, Rice University, Houston, Texas 77251
| | - Esther J Lee
- Department of Bioengineering, Rice University, Houston, Texas 77251
| | - Elisa C Clark
- Department of Bioengineering, Rice University, Houston, Texas 77251
| | - Antonios G Mikos
- Department of Chemical and Biomolecular Engineering, Rice University, Houston, Texas 77251
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21
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Allogeneic Umbilical Cord-Derived Mesenchymal Stem Cells as a Potential Source for Cartilage and Bone Regeneration: An In Vitro Study. Stem Cells Int 2017; 2017:1732094. [PMID: 29358953 PMCID: PMC5735324 DOI: 10.1155/2017/1732094] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Revised: 10/02/2017] [Accepted: 10/11/2017] [Indexed: 02/06/2023] Open
Abstract
Umbilical cord (UC) may represent an attractive cell source for allogeneic mesenchymal stem cell (MSC) therapy. The aim of this in vitro study is to investigate the chondrogenic and osteogenic potential of UC-MSCs grown onto tridimensional scaffolds, to identify a possible clinical relevance for an allogeneic use in cartilage and bone reconstructive surgery. Chondrogenic differentiation on scaffolds was confirmed at 4 weeks by the expression of sox-9 and type II collagen; low oxygen tension improved the expression of these chondrogenic markers. A similar trend was observed in pellet culture in terms of matrix (proteoglycan) production. Osteogenic differentiation on bone-graft-substitute was also confirmed after 30 days of culture by the expression of osteocalcin and RunX-2. Cells grown in the hypertrophic medium showed at 5 weeks safranin o-positive stain and an increased CbFa1 expression, confirming the ability of these cells to undergo hypertrophy. These results suggest that the UC-MSCs isolated from minced umbilical cords may represent a valuable allogeneic cell population, which might have a potential for orthopaedic tissue engineering such as the on-demand cell delivery using chondrogenic, osteogenic, and endochondral scaffold. This study may have a clinical relevance as a future hypothetical option for allogeneic single-stage cartilage repair and bone regeneration.
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Gao P, Han P, Jiang D, Yang S, Cui Q, Li Z. Effects of the donor age on proliferation, senescence and osteogenic capacity of human urine-derived stem cells. Cytotechnology 2017; 69:751-763. [PMID: 28409292 PMCID: PMC5595747 DOI: 10.1007/s10616-017-0084-5] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Accepted: 03/15/2017] [Indexed: 12/22/2022] Open
Abstract
To study the effects of the donor age on the application potential of human urine-derived stem cells (hUSCs) in bone tissue engineering, by comparing proliferation, senescence and osteogenic differentiation of hUSCs originated from volunteers with different ages. The urine samples were collected from 19 healthy volunteers (6 cases from children group aged from 5 to 14, 5 cases from middle-aged group aged from 30 to 40, and 8 cases from the elder group aged from 65 to 75), and hUSCs were isolated and cultured. The cell morphology was observed by microscope and the cell surface markers were identified by flow cytometry. Their abilities to undergo osteogenic, adipogenic and chondrogenic differentiation were determined in vitro, and cell proliferation analyses were performed using Cell Counting Kit-8 (CCK8) Assay. The senescence of hUSCs among three groups was assessed by senescence-associated β galactosidase staining. After osteogenic differentiation, the alkaline phosphatase (ALP) activity of hUSCs was measured and expression of osteogenic-related runt-related transcription factor 2 (RUNX2) and osteocalcin (OCN) was determined by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. The hUSCs isolated from urine samples were adherent cells displayed "rice gain"-like and "spindle-shaped" morphology, expressing surface markers of mesenchymal stem cells (MSCs) (CD73, CD90, CD105) and the peripheral cell marker (CD146), but not hematopoietic stem cell markers (CD34, CD45) or the embryonic stem cell marker (OCT3/4). The obtained hUSCs could be induced into osteogenic, adipogenic or chondrogenic differentiation. The hUSCs from the children group showed higher proliferation and lower tendency to senescence than those from the middle-aged and elder groups. After osteogenic induction, the ALP activity and RUNX2 and OCN expression of hUSCs from the children group were higher than those from the elder group. While no significant differences were observed when comparing the middle-aged group with the children group or the elder group. Donor age could influence the potency of hUSCs on proliferation, senescence and capacity of osteogenic differentiation. hUSCs from children group have shown higher proliferation, lower tendency to senescence, and stronger osteogenic capacity, which means to be more suitable for basic research and have better clinical application. Furthermore, hUSCs from all groups suggest the application potential in bone tissue engineering as seed cells.
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Affiliation(s)
- Peng Gao
- Department of Pediatric Surgery, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China
- Department of Pediatric Surgery, Harbin Children's Hospital, Harbin, China
| | - Peilin Han
- Department of Pediatric Surgery, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Dapeng Jiang
- Department of Pediatric Surgery, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China
- Department of Pediatric Urology, Shanghai Xinhua Hospital, Shanghai, China
| | - Shulong Yang
- Department of Pediatric Surgery, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Qingbo Cui
- Department of Pediatric Surgery, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zhaozhu Li
- Department of Pediatric Surgery, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China.
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Kashte S, Jaiswal AK, Kadam S. Artificial Bone via Bone Tissue Engineering: Current Scenario and Challenges. Tissue Eng Regen Med 2017; 14:1-14. [PMID: 30603457 PMCID: PMC6171575 DOI: 10.1007/s13770-016-0001-6] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2015] [Revised: 04/11/2016] [Accepted: 04/27/2016] [Indexed: 12/18/2022] Open
Abstract
Bone provides mechanical support, and flexibility to the body as a structural frame work along with mineral storage, homeostasis, and blood pH regulation. The repair and/or replacement of injured or defective bone with healthy bone or bone substitute is a critical problem in orthopedic treatment. Recent advances in tissue engineering have shown promising results in developing bone material capable of substituting the conventional autogenic or allogenic bone transplants. In the present review, we have discussed natural and synthetic scaffold materials such as metal and metal alloys, ceramics, polymers, etc. which are widely being used along with their cellular counterparts such as stem cells in bone tissue engineering with their pros and cons.
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Affiliation(s)
- Shivaji Kashte
- Department of Biosciences and Technology, Defence Institute of Advanced Technology, Girinagar, Pune, MS 411025 India
- Center for Interdisciplinary Research, D. Y. Patil University, Kolhapur, 416006 India
| | - Amit Kumar Jaiswal
- Center for Biomaterials, Cellular and Molecular Theranostics, VIT University, Vellore, 632104 India
| | - Sachin Kadam
- Center for Interdisciplinary Research, D. Y. Patil University, Kolhapur, 416006 India
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Kanie K, Kurimoto R, Tian J, Ebisawa K, Narita Y, Honda H, Kato R. Screening of Osteogenic-Enhancing Short Peptides from BMPs for Biomimetic Material Applications. MATERIALS (BASEL, SWITZERLAND) 2016; 9:E730. [PMID: 28773850 PMCID: PMC5457080 DOI: 10.3390/ma9090730] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Revised: 08/17/2016] [Accepted: 08/19/2016] [Indexed: 01/13/2023]
Abstract
Bone regeneration is an important issue in many situations, such as bone fracture and surgery. Umbilical cord mesenchymal stem cells (UC-MSCs) are promising cell sources for bone regeneration. Bone morphogenetic proteins and their bioactive peptides are biomolecules known to enhance the osteogenic differentiation of MSCs. However, fibrosis can arise during the development of implantable biomaterials. Therefore, it is important to control cell organization by enhancing osteogenic proliferation and differentiation and inhibiting fibroblast proliferation. Thus, we focused on the screening of such osteogenic-enhancing peptides. In the present study, we developed new peptide array screening platforms to evaluate cell proliferation and alkaline phosphatase activity in osteoblasts, UC-MSCs and fibroblasts. The conditions for the screening platform were first defined using UC-MSCs and an osteogenic differentiation peptide known as W9. Next, in silico screening to define the candidate peptides was carried out to evaluate the homology of 19 bone morphogenetic proteins. Twenty-five candidate 9-mer peptides were selected for screening. Finally, the screening of osteogenic-enhancing (osteogenic cell-selective proliferation and osteogenic differentiation) short peptide was carried out using the peptide array method, and three osteogenic-enhancing peptides were identified, confirming the validity of this screening.
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Affiliation(s)
- Kei Kanie
- Department of Basic Medicinal Sciences, Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Aichi, Japan.
| | - Rio Kurimoto
- Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8577, Ibaraki, Japan.
- Biomaterials Unit, International Center for Materials Nanoarchitectonics (WPI-MANA), National Institute for Materials Science (NIMS), 1-1 Namiki, Tsukuba 305-0044, Ibaraki, Japan.
| | - Jing Tian
- Department of Biotechnology, Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8603, Aichi, Japan.
| | - Katsumi Ebisawa
- Department of Plastic and Reconstructive Surgery, Nagoya University Graduate School of Medicine, 65 Turumai-cho, Showa-ku, Nagoya 466-8550, Aichi, Japan.
| | - Yuji Narita
- Department of Cardiac Surgery, Nagoya University Graduate School of Medicine, 65 Turumai-cho, Showa-ku, Nagoya 466-8550, Aichi, Japan.
| | - Hiroyuki Honda
- Department of Biotechnology, Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8603, Aichi, Japan.
| | - Ryuji Kato
- Department of Basic Medicinal Sciences, Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Aichi, Japan.
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Phetfong J, Sanvoranart T, Nartprayut K, Nimsanor N, Seenprachawong K, Prachayasittikul V, Supokawej A. Osteoporosis: the current status of mesenchymal stem cell-based therapy. Cell Mol Biol Lett 2016; 21:12. [PMID: 28536615 PMCID: PMC5414670 DOI: 10.1186/s11658-016-0013-1] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2015] [Accepted: 01/25/2016] [Indexed: 12/21/2022] Open
Abstract
Osteoporosis, or bone loss, is a progressive, systemic skeletal disease that affects millions of people worldwide. Osteoporosis is generally age related, and it is underdiagnosed because it remains asymptomatic for several years until the development of fractures that confine daily life activities, particularly in elderly people. Most patients with osteoporotic fractures become bedridden and are in a life-threatening state. The consequences of fracture can be devastating, leading to substantial morbidity and mortality of the patients. The normal physiologic process of bone remodeling involves a balance between bone resorption and bone formation during early adulthood. In osteoporosis, this process becomes imbalanced, resulting in gradual losses of bone mass and density due to enhanced bone resorption and/or inadequate bone formation. Several growth factors underlying age-related osteoporosis and their signaling pathways have been identified, such as osteoprotegerin (OPG)/receptor activator of nuclear factor B (RANK)/RANK ligand (RANKL), bone morphogenetic protein (BMP), wingless-type MMTV integration site family (Wnt) proteins and signaling through parathyroid hormone receptors. In addition, the pathogenesis of osteoporosis has been connected to genetics. The current treatment of osteoporosis predominantly consists of antiresorptive and anabolic agents; however, the serious adverse effects of using these drugs are of concern. Cell-based replacement therapy via the use of mesenchymal stem cells (MSCs) may become one of the strategies for osteoporosis treatment in the future.
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Affiliation(s)
- Jitrada Phetfong
- Department of Clinical Microscopy, Faculty of Medical Technology, Mahidol University, Phuttamonthon, Salaya, Nakhon Pathom 73170 Thailand
| | - Tanwarat Sanvoranart
- Department of Clinical Microscopy, Faculty of Medical Technology, Mahidol University, Phuttamonthon, Salaya, Nakhon Pathom 73170 Thailand
| | - Kuneerat Nartprayut
- Department of Clinical Microscopy, Faculty of Medical Technology, Mahidol University, Phuttamonthon, Salaya, Nakhon Pathom 73170 Thailand
| | - Natakarn Nimsanor
- Department of Clinical Microscopy, Faculty of Medical Technology, Mahidol University, Phuttamonthon, Salaya, Nakhon Pathom 73170 Thailand
| | - Kanokwan Seenprachawong
- Department of Clinical Microscopy, Faculty of Medical Technology, Mahidol University, Phuttamonthon, Salaya, Nakhon Pathom 73170 Thailand
| | - Virapong Prachayasittikul
- Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Phuttamonthon, Salaya, Nakhon Pathom 73170 Thailand
| | - Aungkura Supokawej
- Department of Clinical Microscopy, Faculty of Medical Technology, Mahidol University, Phuttamonthon, Salaya, Nakhon Pathom 73170 Thailand
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Ye B, Luo X, Li Z, Zhuang C, Li L, Lu L, Ding S, Tian J, Zhou C. Rapid biomimetic mineralization of collagen fibrils and combining with human umbilical cord mesenchymal stem cells for bone defects healing. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2016; 68:43-51. [PMID: 27523994 DOI: 10.1016/j.msec.2016.05.104] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Revised: 04/30/2016] [Accepted: 05/23/2016] [Indexed: 12/17/2022]
Abstract
Collagen biomineralization is regulated by complicated interactions between the collagen matrix and non-collagenous extracellular proteins. Here, the use of sodium tripolyphosphate to simulate the templating functional motif of the C-terminal fragment of non-collagenous proteins is reported, and a low molecular weight polyacrylic acid served as a sequestration agent to stabilize amorphous calcium phosphate into nanoprecursors. Self-assembled collagen fibrils served as a fixed template for achieving rapid biomimetic mineralization in vitro. Results demonstrated that, during the mineralization process, intrafibrillar and extrafibrillar hydroxyapatite mineral with collagen fibrils formed and did so via bottom-up nanoparticle assembly based on the non-classical crystallization approach in the presence of these dual biomimetic functional analogues. In vitro human umbilical cord mesenchymal stem cell (hUCMSC) culture found that the mineralized scaffolds have a better cytocompatibility in terms of cell viability, adhesion, proliferation, and differentiation into osteoblasts. A rabbit femoral condyle defect model was established to confirm the ability of the n-HA/collagen scaffolds to facilitate bone regeneration and repair. The images of gross anatomy, MRI, CT and histomorphology taken 6 and 12weeks after surgery showed that the biomimetic mineralized collagen scaffolds with hUCMSCs can promote the healing speed of bone defects in vivo, and both of the scaffolds groups performing better than the bone defect control group. As new bone tissue formed, the scaffolds degraded and were gradually absorbed. All these results demonstrated that both of the scaffolds and cells have better histocompatibility.
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Affiliation(s)
- Bihua Ye
- Department of Material Science and Engineering, Engineering Research Center of Artificial Organs and Materials, Jinan University, Guangzhou 510632, China
| | - Xueshi Luo
- Department of Material Science and Engineering, Engineering Research Center of Artificial Organs and Materials, Jinan University, Guangzhou 510632, China
| | - Zhiwen Li
- Department of Material Science and Engineering, Engineering Research Center of Artificial Organs and Materials, Jinan University, Guangzhou 510632, China
| | - Caiping Zhuang
- Department of Anesthesiology, Huizhou Central People's Hospital, Huizhou 516001, China
| | - Lihua Li
- Department of Material Science and Engineering, Engineering Research Center of Artificial Organs and Materials, Jinan University, Guangzhou 510632, China.
| | - Lu Lu
- Department of Material Science and Engineering, Engineering Research Center of Artificial Organs and Materials, Jinan University, Guangzhou 510632, China
| | - Shan Ding
- Department of Material Science and Engineering, Engineering Research Center of Artificial Organs and Materials, Jinan University, Guangzhou 510632, China
| | - Jinhuan Tian
- Department of Material Science and Engineering, Engineering Research Center of Artificial Organs and Materials, Jinan University, Guangzhou 510632, China
| | - Changren Zhou
- Department of Material Science and Engineering, Engineering Research Center of Artificial Organs and Materials, Jinan University, Guangzhou 510632, China.
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Current View on Osteogenic Differentiation Potential of Mesenchymal Stromal Cells Derived from Placental Tissues. Stem Cell Rev Rep 2016; 11:570-85. [PMID: 25381565 PMCID: PMC4493719 DOI: 10.1007/s12015-014-9569-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Mesenchymal stromal cells (MSC) isolated from human term placental tissues possess unique characteristics, including their peculiar immunomodulatory properties and their multilineage differentiation potential. The osteogenic differentiation capacity of placental MSC has been widely disputed, and continues to be an issue of debate. This review will briefly discuss the different MSC populations which can be obtained from different regions of human term placenta, along with their unique properties, focusing specifically on their osteogenic differentiation potential. We will present the strategies used to enhance osteogenic differentiation potential in vitro, such as through the selection of subpopulations more prone to differentiate, the modification of the components of osteo-inductive medium, and even mechanical stimulation. Accordingly, the applications of three-dimensional environments in vitro and in vivo, such as non-synthetic, polymer-based, and ceramic scaffolds, will also be discussed, along with results obtained from pre-clinical studies of placental MSC for the regeneration of bone defects and treatment of bone-related diseases.
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Electrospun poly (3-hydroxybutyrate-co-3-hydroxyvalerate)/hydroxyapatite scaffold with unrestricted somatic stem cells for bone regeneration. ASAIO J 2016; 61:357-65. [PMID: 25710767 DOI: 10.1097/mat.0000000000000205] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The combination of scaffolds and cells can be useful in tissue reconstruction. In this study, nanofibrous poly (3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV)/nanohydroxyapatite (nano-HAp) scaffolds, filled with unrestricted somatic stem cells (USSCs), were used for healing calvarial bone in rat model. The healing effects of these scaffolds, with and without stem cells, in bone regeneration were investigated by computed tomography (CT) analysis and pathology assays after 28 days of grafting. The results of CT analysis showed that bone regeneration on the scaffolds, and the amounts of regenerated new bone for polymer/nano-HAp scaffold with USSC, was significantly greater than the scaffold without cell and untreated control samples. Therefore, the combination of scaffold especially with USSC could be considered as a useful method for bone regeneration.
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Noh MJ, Lee KH. Orthopedic cellular therapy: An overview with focus on clinical trials. World J Orthop 2015; 6:754-61. [PMID: 26601056 PMCID: PMC4644862 DOI: 10.5312/wjo.v6.i10.754] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2015] [Revised: 08/22/2015] [Accepted: 09/25/2015] [Indexed: 02/06/2023] Open
Abstract
In this editorial, the authors tried to evaluate the present state of cellular therapy in orthopedic field. The topics the authors try to cover include not only the clinical trials but the various research areas as well. Both the target diseases for cellular therapy and the target cells were reviewed. New methods to activate the cells were interesting to review. Most advanced clinical trials were also included because several of them have advanced to phase III clinical trials. In the orthopedic field, there are many diseases with a definite treatment gap at this time. Because cellular therapies can regenerate damaged tissues, there is a possibility for cellular therapies to become disease modifying drugs. It is not clear whether cellular therapies will become the standard of care in any of the orthopedic disorders, however the amount of research being performed and the number of clinical trials that are on-going make the authors believe that cellular therapies will become important treatment modalities within several years.
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Si JW, Wang XD, Shen SGF. Perinatal stem cells: A promising cell resource for tissue engineering of craniofacial bone. World J Stem Cells 2015; 7:149-159. [PMID: 25621114 PMCID: PMC4300925 DOI: 10.4252/wjsc.v7.i1.149] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2014] [Revised: 08/28/2014] [Accepted: 09/17/2014] [Indexed: 02/06/2023] Open
Abstract
In facing the mounting clinical challenge and suboptimal techniques of craniofacial bone defects resulting from various conditions, such as congenital malformations, osteomyelitis, trauma and tumor resection, the ongoing research of regenerative medicine using stem cells and concurrent advancement in biotechnology have shifted the focus from surgical reconstruction to a novel stem cell-based tissue engineering strategy for customized and functional craniofacial bone regeneration. Given the unique ontogenetical and cell biological properties of perinatal stem cells, emerging evidence has suggested these extraembryonic tissue-derived stem cells to be a promising cell source for extensive use in regenerative medicine and tissue engineering. In this review, we summarize the current achievements and obstacles in stem cell-based craniofacial bone regeneration and subsequently we address the characteristics of various types of perinatal stem cells and their novel application in tissue engineering of craniofacial bone. We propose the promising feasibility and scope of perinatal stem cell-based craniofacial bone tissue engineering for future clinical application.
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Osteoblastic differentiation of Wharton jelly biopsy specimens and their mesenchymal stromal cells after serum-free culture. Plast Reconstr Surg 2014; 134:59e-69e. [PMID: 25028857 DOI: 10.1097/prs.0000000000000305] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Cleft lip and cleft palate are increasingly being detected by prenatal ultrasound, which raises the opportunity of using the patient's own osteogenicity from umbilical cord mesenchymal cells for bony repair. The authors address the growth of the cells under a fully defined and regulated protocol. METHODS Wharton jelly-derived mesenchymal stromal cells were isolated and expanded as a monolayer with defined serum-free medium. Osteoblastic differentiation was tested in the cells and in the entire Wharton jelly biopsy specimens. The serum-free-cultured cells were included in hydroxyapatite granule-fibrin constructs and, without predifferentiation, subcutaneously implanted into immunoincompetent mice. RESULTS Isolation and expansion of Wharton jelly-derived mesenchymal stromal cells were consistently successful under serum-free conditions, and the cells expressed standard mesenchymal stromal cell markers. The serum-free-cultivated cells produced a mineralized extracellular matrix under osteogenic differentiation, with a significant increase of osteoblastic lineage gene expression (Hox-A10 and Runx2) and an up-regulation of downstream osteogenic genes (OSX, OCN, ALPL, and BSP2). In vivo, they formed a dense matrix adjacent to the granules after 8 weeks, but no lamellar bone. serum-free-cultivated entire Wharton jelly biopsy specimens produced a mineralized extracellular matrix within the collagen matrix of the Wharton jelly. CONCLUSIONS The osteogenic differentiation potential of Wharton jelly-derived mesenchymal stromal cells was maintained under serum-free isolation and expansion techniques. The cells without predifferentiation form a dense collagen matrix but not bone in vivo. Moreover, entire Wharton jelly biopsy specimens showed periosteal-like mineralization under osteogenic differentiation, which offers new options for autologous bone tissue engineering, including cleft palate surgery.
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Tavakolinejad S, Ebrahimzadeh Bidskan A, Ashraf H, Hamidi Alamdari D. A glance at methods for cleft palate repair. IRANIAN RED CRESCENT MEDICAL JOURNAL 2014; 16:e15393. [PMID: 25593724 PMCID: PMC4270645 DOI: 10.5812/ircmj.15393] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/20/2013] [Revised: 01/13/2014] [Accepted: 01/21/2014] [Indexed: 01/17/2023]
Abstract
Context: Cleft palate is the second most common birth defect and is considered as a challenge for pediatric plastic surgeons. There is still a general lack of a standard protocol and patients often require multiple surgical interventions during their lifetime along with disappointing results. Evidence Acquisition: PubMed search was undertaken using search terms including 'cleft palate repair', 'palatal cleft closure', 'cleft palate + stem cells', 'cleft palate + plasma rich platelet', 'cleft palate + scaffold', 'palatal tissue engineering', and 'bone tissue engineering'. The found articles were included if they defined a therapeutic strategy and/or assessed a new technique. Results: We reported a summary of the key-points concerning cleft palate development, the genes involving this defect, current therapeutic strategies, recently novel aspects, and future advances in treatments for easy and fast understanding of the concepts, rather than a systematic review. In addition, the results were integrated with our recent experience. Conclusions: Tissue engineering may open a new window in cleft palate reconstruction. Stem cells and growth factors play key roles in this field.
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Affiliation(s)
- Sima Tavakolinejad
- Department of Anatomy and Cell Biology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, IR Iran
| | - Alireza Ebrahimzadeh Bidskan
- Department of Anatomy and Cell Biology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, IR Iran
| | - Hami Ashraf
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, IR Iran
| | - Daryoush Hamidi Alamdari
- Biochemistry and Nutrition Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, IR Iran
- Corresponding Author: Daryoush Hamidi Alamdari, Biochemistry and Nutrition Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, IR Iran. Tel: +98-9151017650, E-mail:
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Kouroupis D, Churchman SM, English A, Emery P, Giannoudis PV, McGonagle D, Jones EA. Assessment of umbilical cord tissue as a source of mesenchymal stem cell/endothelial cell mixtures for bone regeneration. Regen Med 2014; 8:569-81. [PMID: 23998751 DOI: 10.2217/rme.13.47] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
AIM To enumerate and characterize mesenchymal stem cells (MSCs) and endothelial cells (ECs) in umbilical cord (UC) tissue digests. MATERIALS & METHODS Cultured UC cells were characterized phenotypically, and functionally by using 48-gene arrays. Native MSCs and ECs were enumerated using flow cytometry. RESULTS Compared with bone marrow (BM) MSCs, UC MSCs displayed significantly lower (range 4-240-fold) basal levels of bone-related transcripts, but their phenotypes were similar (CD73⁺, CD105⁺, CD90⁺, CD45⁻ and CD31⁻). UC MSCs responded well to osteogenic induction, but day 21 postinduction levels remained below those achieved by BM MSCs. The total yield of native UC MSCs (CD90⁺, CD45⁻ and CD235α⁻) and ECs (CD31⁺, CD45⁻ and CD235α⁻) exceeded 150 and 15 million cells/donation, respectively. Both UC MSCs and ECs expressed CD146. CONCLUSION While BM MSCs are more predisposed to osteogenesis, UC tissue harbors large numbers of MSCs and ECs; such minimally manipulated 'off-the-shelf' cellular mixtures can be used for regenerating bone in patients with compromised vascular supply.
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Affiliation(s)
- Dimitrios Kouroupis
- Leeds Institute of Rheumatic & Musculoskeletal Medicine, University of Leeds, Leeds, UK
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Biazar E. Use of umbilical cord and cord blood-derived stem cells for tissue repair and regeneration. Expert Opin Biol Ther 2014; 14:301-10. [PMID: 24456082 DOI: 10.1517/14712598.2014.867943] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Potential use of umbilical cord (UC) is one of the most exciting frontiers in medicine for repairing damaged tissues. UC and cord blood-derived stem cells are the world's largest potential sources of stem cells. UC contains a mixture of stem and progenitor cells at different lineage commitment stages and UC has been verified as a candidate for cell-based therapies and tissue engineering applications due to the capability of these cells for extensive self-renewal and multi-lineage character in differentiation potential. AREAS COVERED UC-based repair or regeneration of organs (i.e., heart, nerve, skin, etc.) is a high-priority research worldwide. EXPERT OPINION The aim of this review is to summarize the knowledge about UC with main focus on its applications for tissue repair and regeneration.
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Affiliation(s)
- Esmaeil Biazar
- Islamic Azad University, Department of Biomedical Engineering, Tonekabon Branch , Tonekabon , Iran +00981924271105 ;
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Ma J, Both SK, Yang F, Cui FZ, Pan J, Meijer GJ, Jansen JA, van den Beucken JJJP. Concise review: cell-based strategies in bone tissue engineering and regenerative medicine. Stem Cells Transl Med 2013; 3:98-107. [PMID: 24300556 DOI: 10.5966/sctm.2013-0126] [Citation(s) in RCA: 114] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Cellular strategies play an important role in bone tissue engineering and regenerative medicine (BTE/RM). Variability in cell culture procedures (e.g., cell types, cell isolation and expansion, cell seeding methods, and preculture conditions before in vivo implantation) may influence experimental outcome. Meanwhile, outcomes from initial clinical trials are far behind those of animal studies, which is suggested to be related to insufficient nutrient and oxygen supply inside the BTE/RM constructs as some complex clinical implementations require bone regeneration in too large a quantity. Coculture strategies, in which angiogenic cells are introduced into osteogenic cell cultures, might provide a solution for improving vascularization and hence increasing bone formation for cell-based constructs. So far, preclinical studies have demonstrated that cell-based tissue-engineered constructs generally induce more bone formation compared with acellular constructs. Further, cocultures have been shown to enhance vascularization and bone formation compared with monocultures. However, translational efficacy from animal studies to clinical use requires improvement, and the role implanted cells play in clinical bone regeneration needs to be further elucidated. In view of this, the present review provides an overview of the critical procedures during in vitro and in vivo phases for cell-based strategies (both monoculture and coculture) in BTE/RM to achieve more standardized culture conditions for future studies, and hence enhance bone formation.
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Affiliation(s)
- Jinling Ma
- Department of VIP Service and Department of Oral and Maxillofacial Surgery, Beijing Stomatological Hospital, Capital Medical University, Beijing, China; Department of Biomaterials and Department of Oral and Maxillofacial Surgery, Radboud University Medical Center, Nijmegen, The Netherlands; State Key Laboratory of New Ceramics and Fine Processing, Department of Materials Science & Engineering, Tsinghua University, Beijing, China
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Biazar E, Heidari Keshel S, Rezaei Tavirani M, Jahandideh R. Bone formation in calvarial defects by injectable nanoparticular scaffold loaded with stem cells. Expert Opin Biol Ther 2013; 13:1653-62. [PMID: 24088030 DOI: 10.1517/14712598.2013.840284] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVE Calcium phosphates are one of biomaterials that are used for bone regeneration. In this study, calcium phosphate nanoparticles such as hydroxyapatite (HA)/fluorapatite (FA),with chitosan gel filled with unrestricted somatic stem cells (USSCs) were used for healing calvarial bone in rat model. METHODS The healing effects of these injectable scaffolds, with and without stem cells, in bone regeneration were investigated by computed tomography (CT) analysis and pathology assays after 28 days of grafting. RESULTS The results of CT analysis showed that bone regeneration on the scaffolds, and the amounts of regenerated new bone for USSC scaffold were significantly greater than the scaffold without cell and untreated controls. CONCLUSION Therefore, the combination of scaffold especially with USSC could be considered as a useful method for bone regeneration.
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Affiliation(s)
- Esmaeil Biazar
- Islamic Azad University, Department of Biomaterial Engineering , Tonekabon Branch , Iran +98 1924274415 ; +98 192 427 4411 ;
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Jung IH, Kwon BS, Kim SH, Shim HE, Jun CM, Yun JH. Optimal Medium Formulation for the Long-Term Expansion and Maintenance of Human Periodontal Ligament Stem Cells. J Periodontol 2013; 84:1434-44. [DOI: 10.1902/jop.2013.120541] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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Chen W, Liu J, Manuchehrabadi N, Weir MD, Zhu Z, Xu HHK. Umbilical cord and bone marrow mesenchymal stem cell seeding on macroporous calcium phosphate for bone regeneration in rat cranial defects. Biomaterials 2013; 34:9917-25. [PMID: 24054499 DOI: 10.1016/j.biomaterials.2013.09.002] [Citation(s) in RCA: 118] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2013] [Accepted: 09/02/2013] [Indexed: 02/08/2023]
Abstract
Human umbilical cord mesenchymal stem cells (hUCMSCs) are inexhaustible and can be harvested at a low cost without an invasive procedure. However, there has been no report on comparing hUCMSCs with human bone marrow MSCs (hBMSCs) for bone regeneration in vivo. The aim of this study was to investigate hUCMSC and hBMSC seeding on macroporous calcium phosphate cement (CPC), and to compare their bone regeneration in critical-sized cranial defects in rats. Cell attachment, osteogenic differentiation and mineral synthesis on RGD-modified macroporous CPC were investigated in vitro. Scaffolds with cells were implanted in 8-mm defects of athymic rats. Bone regeneration was investigated via micro-CT and histological analysis at 4, 12, and 24 weeks. Three groups were tested: CPC with hUCMSCs, CPC with hBMSCs, and CPC control without cells. Percentage of live cells and cell density on CPC in vitro were similarly good for hUCMSCs and hBMSCs. Both cells had high osteogenic expressions of alkaline phosphatase, osteocalcin, collagen I, and Runx2. Bone mineral density and trabecular thickness in hUCMSC and hBMSC groups in vivo were greater than those of CPC control group. New bone amount for hUCMSC-CPC and hBMSC-CPC constructs was increased by 57% and 88%, respectively, while blood vessel density was increased by 15% and 20%, than CPC control group at 24 weeks. hUCMSC-CPC and hBMSC-CPC groups generally had statistically similar bone mineral density, new bone amount and vessel density. In conclusion, hUCMSCs seeded on CPC were shown to match the bone regeneration efficacy of hBMSCs in vivo for the first time. Both hUCMSC-CPC and hBMSC-CPC constructs generated much more new bone and blood vessels than CPC without cells. Macroporous RGD-grafted CPC with stem cell seeding is promising for craniofacial and orthopedic repairs.
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Affiliation(s)
- Wenchuan Chen
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China; Biomaterials & Tissue Engineering Division, Department of Endodontics, Prosthodontics and Operative Dentistry, University of Maryland Dental School, Baltimore, MD 21201, USA
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Wang F, Zhang YC, Zhou H, Guo YC, Su XX. Evaluation ofin vitroandin vivoosteogenic differentiation of nano-hydroxyapatite/chitosan/poly(lactide-co-glycolide) scaffolds with human umbilical cord mesenchymal stem cells. J Biomed Mater Res A 2013; 102:760-8. [PMID: 23564567 DOI: 10.1002/jbm.a.34747] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2013] [Revised: 03/17/2013] [Accepted: 04/02/2013] [Indexed: 11/09/2022]
Affiliation(s)
- Fei Wang
- The Department of Orthodontics; the Affiliated Stomatological Hospital of Xi'an Jiaotong University; Xian 710004 China
| | - Yin-Cheng Zhang
- The Department of Orthodontics; the Affiliated Stomatological Hospital of Xi'an Jiaotong University; Xian 710004 China
| | - Hong Zhou
- The Department of Orthodontics; the Affiliated Stomatological Hospital of Xi'an Jiaotong University; Xian 710004 China
| | - Yu-Cheng Guo
- The Department of Orthodontics; the Affiliated Stomatological Hospital of Xi'an Jiaotong University; Xian 710004 China
| | - Xiao-Xia Su
- The Department of Orthodontics; the Affiliated Stomatological Hospital of Xi'an Jiaotong University; Xian 710004 China
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Jo CH, Yoon PW, Kim H, Kang KS, Yoon KS. Comparative evaluation of in vivo osteogenic differentiation of fetal and adult mesenchymal stem cell in rat critical-sized femoral defect model. Cell Tissue Res 2013; 353:41-52. [PMID: 23624634 DOI: 10.1007/s00441-013-1619-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2012] [Accepted: 03/13/2013] [Indexed: 11/27/2022]
Abstract
Mesenchymal stem cells (MSCs) can be obtained from various sources. MSCs from different origins appear to have different preferences for differentiation. In this study, we have compared the in vivo osteogenic potential of adult MSCs from adipose tissue (AT) and bone marrow (BM) with fetal MSCs from umbilical cord (UC) and umbilical cord blood (UCB) by using a rat critical-sized femoral defect model. We have also sought to determine whether pretreatment with an osteogenic medium promotes osteogenesis in MSCs. Study groups were divided as follows: (1) defect only, (2) scaffold only, (3) AT MSCs in scaffolds, (4) BM MSCs in scaffolds, (5) UC MSCs in scaffolds and (6) UCB MSCs in scaffolds. Groups with MSCs were further divided with respect to their pretreatment. At 12 weeks after surgery, in vivo osteogenesis was measured radiographically and by micro-computed tomography (CT). Based on quantitative assessment by micro-CT, no significant difference of the mean bone volume fraction value (BV/TV) was seen between adult MSCs (AT and BM MSCs) and fetal MSCs (UC and UCB MSCs). The mean BV/TVs were significantly higher in non-pretreated BM MSC (14.2±1.4%) and UCB MSC (14.0±1.2%) and pretreated UC MSC (14.8±2.0%) than in those with the scaffold only (11.3±1.3%; P<0.05). In addition, AT (from 10.4±1.2% to 13.1±2.2%) and UC (from 10.3±0.7% to 14.8±2.0%) MSCs from solid tissues showed a significant increase in the mean BV/TV with pretreatment (P<0.05). In contrast, BM MSC (from 14.2±1.4% to 10.9±1.2%) and UCB MSC (from 14.0±1.2% to 11.6±1.0%) from non-solid tissues showed a significant decrease with pretreatment (P<0.05).
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Affiliation(s)
- Chris Hyunchul Jo
- Department of Orthopedic Surgery, Seoul National University Boramae Hospital, Seoul National University College of Medicine, 20 Boramae-Ro, 5-Gil, Dongjak-Gu, Seoul, 156-707, South Korea.
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Comparison of explant-derived and enzymatic digestion-derived MSCs and the growth factors from Wharton's jelly. BIOMED RESEARCH INTERNATIONAL 2013; 2013:428726. [PMID: 23653895 PMCID: PMC3638666 DOI: 10.1155/2013/428726] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/07/2012] [Revised: 02/12/2013] [Accepted: 03/01/2013] [Indexed: 01/31/2023]
Abstract
Wharton's jelly is not only one of the most promising tissue sources for mesenchymal stem cells (MSCs) but also a source of natural growth factors. To prove that we can get both natural growth factors and MSCs from Wharton's jelly, we compared cellular characteristics and the level of basic fibroblast growth factor (bFGF) from samples using the explant culture method to those derived from the traditional enzymatic culture method. The levels of bFGF were 27.0 ± 11.7 ng/g on day 3, 15.6 ± 11.1 ng/g on day 6, and decreased to 2.6 ± 1.2 ng/g on day 14. The total amount of bFGF released was 55.0 ± 25.6 ng/g on explant culture. Compared with the traditional enzymatic digestion method, the explant culture method showed a tendency to release higher levels of bFGF in supernatant media for the first week of culture, and the higher cellular yield at passage 0 (4.89 ± 3.2 × 105/g versus 1.75 ± 2.2 × 105/g, P = 0.01). In addition, the genes related to mitosis were upregulated in the explant-derived MSCs.
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Lindenmair A, Hatlapatka T, Kollwig G, Hennerbichler S, Gabriel C, Wolbank S, Redl H, Kasper C. Mesenchymal stem or stromal cells from amnion and umbilical cord tissue and their potential for clinical applications. Cells 2012; 1:1061-88. [PMID: 24710543 PMCID: PMC3901122 DOI: 10.3390/cells1041061] [Citation(s) in RCA: 86] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2012] [Revised: 10/29/2012] [Accepted: 11/05/2012] [Indexed: 01/08/2023] Open
Abstract
Mesenchymal stem or stromal cells (MSC) have proven to offer great promise for cell-based therapies and tissue engineering applications, as these cells are capable of extensive self-renewal and display a multilineage differentiation potential. Furthermore, MSC were shown to exhibit immunomodulatory properties and display supportive functions through parakrine effects. Besides bone marrow (BM), still today the most common source of MSC, these cells were found to be present in a variety of postnatal and extraembryonic tissues and organs as well as in a large variety of fetal tissues. Over the last decade, the human umbilical cord and human amnion have been found to be a rich and valuable source of MSC that is bio-equivalent to BM-MSC. Since these tissues are discarded after birth, the cells are easily accessible without ethical concerns.
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Affiliation(s)
- Andrea Lindenmair
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, AUVA Research Center, Vienna/Linz 1200, Austria.
| | - Tim Hatlapatka
- Department of Biotechnology, University of Natural Resources and Life Sciences, Vienna 1190, Austria.
| | - Gregor Kollwig
- Department of Biotechnology, University of Natural Resources and Life Sciences, Vienna 1190, Austria.
| | | | | | - Susanne Wolbank
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, AUVA Research Center, Vienna/Linz 1200, Austria.
| | - Heinz Redl
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, AUVA Research Center, Vienna/Linz 1200, Austria.
| | - Cornelia Kasper
- Department of Biotechnology, University of Natural Resources and Life Sciences, Vienna 1190, Austria.
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Zhou H, Chen W, Weir MD, Xu HH. Biofunctionalized calcium phosphate cement to enhance the attachment and osteodifferentiation of stem cells released from fast-degradable alginate-fibrin microbeads. Tissue Eng Part A 2012; 18:1583-95. [PMID: 22435653 PMCID: PMC3419861 DOI: 10.1089/ten.tea.2011.0604] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2011] [Accepted: 03/19/2012] [Indexed: 01/10/2023] Open
Abstract
Stem cell-encapsulating microbeads could be mixed into a paste such as calcium phosphate cement (CPC), where the microbeads could protect the cells from the mixing and injection forces. After being placed, the microbeads could quickly degrade to release the cells throughout the scaffold, while creating macropores. The objectives of this study were to (1) construct alginate-fibrin microbeads encapsulating human umbilical cord mesenchymal stem cells (hUCMSCs) embedded in the surface of novel biofunctionalized CPC and (2) investigate microbead degradation, cell release, and osteodifferentiation on CPC. Hydrogel microbeads were fabricated that encapsulated hUCMSCs at 1×10(6) cells/mL. CPC was biofunctionalized with fibronectin (Fn) and Arg-Gly-Asp (RGD). Four scaffolds were tested: CPC control, CPC mixed with Fn, CPC mixed with RGD, and CPC grafted with RGD. The degradable microbeads released hUCMSCs at 7 days, which attached to CPC. Adding Fn or RGD to CPC greatly improved cell attachment. CPC grafted with RGD showed the fastest cell proliferation, with cell density being ninefold that on CPC control. The released hUCMSCs underwent osteodifferentiation. Alkaline phosphatase, osteocalcin, collagen 1, and runt-related transcription factor 2 (Runx2) gene expression increased by 10 to 30 fold at 7-21 days, compared with day 1. The released cells on CPC synthesized bone minerals, with the mineralization amount at 21 days being two orders of magnitude higher than that at 7 days. In conclusion, alginate-fibrin microbeads embedded in CPC surface were able to quickly release the hUCMSCs that attached to biofunctionalized CPC. Incorporating Fn and RGD into CPC greatly improved cell function, and CPC grafted with RGD had the fastest cell proliferation. The released cells on CPC differentiated into the osteogenic lineage and synthesized bone minerals. The new biofunctionalized CPC with hUCMSC-encapsulating microbeads is promising for bone regeneration applications.
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Affiliation(s)
- Hongzhi Zhou
- Biomaterials & Tissue Engineering Division, Department of Endodontics, Prosthodontics and Operative Dentistry, University of Maryland School of Dentistry, Baltimore, Maryland
- Department of Oral & Maxillofacial Surgery, School of Stomatology, Fourth Military Medical University, Xi'an, China
| | - Wenchuan Chen
- Biomaterials & Tissue Engineering Division, Department of Endodontics, Prosthodontics and Operative Dentistry, University of Maryland School of Dentistry, Baltimore, Maryland
| | - Michael D. Weir
- Biomaterials & Tissue Engineering Division, Department of Endodontics, Prosthodontics and Operative Dentistry, University of Maryland School of Dentistry, Baltimore, Maryland
| | - Hockin H.K. Xu
- Biomaterials & Tissue Engineering Division, Department of Endodontics, Prosthodontics and Operative Dentistry, University of Maryland School of Dentistry, Baltimore, Maryland
- Center for Stem Cell Biology & Regenerative Medicine, University of Maryland School of Medicine, Baltimore, Maryland
- Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland
- Department of Mechanical Engineering, University of Maryland, Baltimore County, Maryland
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Mesenchymal stem cells as a potent cell source for bone regeneration. Stem Cells Int 2012; 2012:980353. [PMID: 22448175 PMCID: PMC3289837 DOI: 10.1155/2012/980353] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2011] [Revised: 11/21/2011] [Accepted: 12/05/2011] [Indexed: 02/07/2023] Open
Abstract
While small bone defects heal spontaneously, large bone defects need surgical intervention for bone transplantation. Autologous bone grafts are the best and safest strategy for bone repair. An alternative method is to use allogenic bone graft. Both methods have limitations, particularly when bone defects are of a critical size. In these cases, bone constructs created by tissue engineering technologies are of utmost importance. Cells are one main component in the manufacture of bone construct. A few cell types, including embryonic stem cells (ESCs), adult osteoblast, and adult stem cells, can be used for this purpose. Mesenchymal stem cells (MSCs), as adult stem cells, possess characteristics that make them good candidate for bone repair. This paper discusses different aspects of MSCs that render them an appropriate cell type for clinical use to promote bone regeneration.
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Cheng Y, Lin Y, Xiong X, Wu S, Lu J, Cheng N. The human umbilical cord: A novel substitute for reconstruction of the extrahepatic bile duct. JOURNAL OF MEDICAL HYPOTHESES AND IDEAS 2012. [DOI: 10.1016/j.jmhi.2012.03.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Chen W, Zhou H, Tang M, Weir MD, Bao C, Xu HHK. Gas-foaming calcium phosphate cement scaffold encapsulating human umbilical cord stem cells. Tissue Eng Part A 2011; 18:816-27. [PMID: 22011243 DOI: 10.1089/ten.tea.2011.0267] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Tissue engineering approaches are promising to meet the increasing need for bone regeneration. Calcium phosphate cement (CPC) can be injected and self-set to form a scaffold with excellent osteoconductivity. The objectives of this study were to develop a macroporous CPC-chitosan-fiber construct containing alginate-fibrin microbeads encapsulating human umbilical cord mesenchymal stem cells (hUCMSCs) and to investigate hUCMSC release from the degrading microbeads and proliferation inside the porous CPC construct. The hUCMSC-encapsulated microbeads were completely wrapped inside the CPC paste, with the gas-foaming porogen creating macropores in CPC to provide for access to culture media. Increasing the porogen content in CPC significantly increased the cell viability, from 49% of live cells in CPC with 0% porogen to 86% of live cells in CPC with 15% porogen. The alginate-fibrin microbeads started to degrade and release the cells inside CPC at 7 days. The released cells started to proliferate inside the macroporous CPC construct. The live cell number inside CPC increased from 270 cells/mm(2) at 1 day to 350 cells/mm(2) at 21 days. The pore volume fraction of CPC increased from 46.8% to 78.4% using the gas-foaming method, with macropore sizes of approximately 100 to 400 μm. The strength of the CPC-chitosan-fiber scaffold at 15% porogen was 3.8 MPa, which approximated the reported 3.5 MPa for cancellous bone. In conclusion, a novel gas-foaming macroporous CPC construct containing degradable alginate-fibrin microbeads was developed that encapsulated hUCMSCs. The cells had good viability while wrapped inside the porous CPC construct. The degradable microbeads in CPC quickly released the cells, which proliferated over time inside the porous CPC. Self-setting, strong CPC with alginate-fibrin microbeads for stem cell delivery is promising for bone tissue engineering applications.
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Affiliation(s)
- Wenchuan Chen
- Biomaterials and Tissue Engineering Division, Department of Endodontics, Prosthodontics and Operative Dentistry, University of Maryland Dental School, Baltimore, Maryland 21201, USA
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Kang MN, Yoon HH, Seo YK, Park JK. Effect of mechanical stimulation on the differentiation of cord stem cells. Connect Tissue Res 2011; 53:149-59. [PMID: 22149641 DOI: 10.3109/03008207.2011.619284] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
In this study, we evaluated the effect of mechanical stimulation on the differentiation of umbilical cord-derived mesenchymal stem cells (UC-MSCs) in osteogenic medium using a Flexcell system that imposed cyclic uniaxial mechanical stimulation at a strain of 0%, 5%, or 10% (5 s of stretch and 15 s of relaxation) for 10 days. The expression of MSC surface antigens (CD73, CD90, and CD105) was significantly decreased as strain increased. Mechanical stimulation inhibited the growth of UC-MSCs and slightly raised lactate dehydrogenase production. Mechanically stimulated groups produced more elastin and sulfated glycosaminoglycan than unstimulated groups and these increases were in proportion to the degree of strain. Reverse transcription-polymerase chain reaction analysis revealed that mechanical stimulation induced a significant increase in the mRNA expression of osteoblast differentiation markers. The mRNA levels of osteopontin, osteonectin, and type I collagen in the 5% and 10% strained groups were significantly higher than those in the 0% strained group. From the Western blot analysis, UC-MSCs produced bone sialoprotein and vimentin in a mechanical strain-dependent manner. Thus, cyclic mechanical loading was able to enhance the differentiation of human UC-MSCs into osteoblast-like cells as determined by osteogenic gene and protein expression. Furthermore, this finding has important implications for the use of the combination of mechanical and osteogenic differentiation media for UC-MSCs in tissue engineering and regenerative medicine.
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Affiliation(s)
- Mi-Na Kang
- Department of Medical Biotechnology, Dongguk University, Seoul, Republic of Korea
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Zhou H, Xu HHK. The fast release of stem cells from alginate-fibrin microbeads in injectable scaffolds for bone tissue engineering. Biomaterials 2011; 32:7503-13. [PMID: 21757229 DOI: 10.1016/j.biomaterials.2011.06.045] [Citation(s) in RCA: 145] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2011] [Accepted: 06/19/2011] [Indexed: 10/17/2022]
Abstract
Stem cell-encapsulating hydrogel microbeads of several hundred microns in size suitable for injection, that could quickly degrade to release the cells, are currently unavailable. The objectives of this study were to: (1) develop oxidized alginate-fibrin microbeads encapsulating human umbilical cord mesenchymal stem cells (hUCMSCs); (2) investigate microbead degradation, cell release, and osteogenic differentiation of the released cells for the first time. Three types of microbeads were fabricated to encapsulate hUCMSCs: (1) Alginate microbeads; (2) oxidized alginate microbeads; (3) oxidized alginate-fibrin microbeads. Microbeads with sizes of about 100-500 μm were fabricated with 1 × 10(6) hUCMSCs/mL of alginate. For the alginate group, there was little microbead degradation, with very few cells released at 21 d. For oxidized alginate, the microbeads started to slightly degrade at 14 d. In contrast, the oxidized alginate-fibrin microbeads started to degrade at 4 d and released the cells. At 7 d, the number of released cells greatly increased and showed a healthy polygonal morphology. At 21 d, the oxidized alginate-fibrin group had a live cell density that was 4-fold that of the oxidized alginate group, and 15-fold that of the alginate group. The released cells had osteodifferentiation, exhibiting highly elevated bone marker gene expressions of ALP, OC, collagen I, and Runx2. Alizarin staining confirmed the synthesis of bone minerals by hUCMSCs, with the mineral concentration at 21 d being 10-fold that at 7 d. In conclusion, fast-degradable alginate-fibrin microbeads with hUCMSC encapsulation were developed that could start to degrade and release the cells at 4 d. The released hUCMSCs had excellent proliferation, osteodifferentiation, and bone mineral synthesis. The alginate-fibrin microbeads are promising to deliver stem cells inside injectable scaffolds to promote tissue regeneration.
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Affiliation(s)
- Hongzhi Zhou
- Biomaterials & Tissue Engineering Division, Department of Endodontics, Prosthodontics and Operative Dentistry, University of Maryland Dental School, Baltimore, MD 21201, USA
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Wang L, Ott L, Seshareddy K, Weiss ML, Detamore MS. Musculoskeletal tissue engineering with human umbilical cord mesenchymal stromal cells. Regen Med 2011; 6:95-109. [PMID: 21175290 DOI: 10.2217/rme.10.98] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Multipotent mesenchymal stromal cells (MSCs) hold tremendous promise for tissue engineering and regenerative medicine, yet with so many sources of MSCs, what are the primary criteria for selecting leading candidates? Ideally, the cells will be multipotent, inexpensive, lack donor site morbidity, donor materials should be readily available in large numbers, immunocompatible, politically benign and expandable in vitro for several passages. Bone marrow MSCs do not meet all of these criteria and neither do embryonic stem cells. However, a promising new cell source is emerging in tissue engineering that appears to meet these criteria: MSCs derived from Wharton's jelly of umbilical cord MSCs. Exposed to appropriate conditions, umbilical cord MSCs can differentiate in vitro along several cell lineages such as the chondrocyte, osteoblast, adipocyte, myocyte, neuronal, pancreatic or hepatocyte lineages. In animal models, umbilical cord MSCs have demonstrated in vivo differentiation ability and promising immunocompatibility with host organs/tissues, even in xenotransplantation. In this article, we address their cellular characteristics, multipotent differentiation ability and potential for tissue engineering with an emphasis on musculoskeletal tissue engineering.
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Affiliation(s)
- Limin Wang
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, MI 48109, USA
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